Koen Venema investigates what best to feed your microbiome

Everything we eat travels through the stomach to our intestines. Anything not absorbed by the body passes through the microbiome. Unsurprisingly, diet therefore affects our gut flora. "But we are still unsure what most ingredients do to individual bacteria or to the composition of the whole microbiome," explains microbiome expert Venema. This is exactly what he and his colleagues at Wageningen University & Research (WUR) want to unravel in order to use diet to promote a healthy microbiome.  

What does a healthy microbiome look like?

"A healthy microbiome is hard to define. We estimate that a person has about 350 different microorganisms in their gut, but everyone has a unique composition. If you compare the microbiome of five hundred people, you won't find a single microorganism that occurs in all of them. What matters most are ‘anomalies’. We know from research that certain microorganisms are linked to health. Enterococcus faecalis, for example, regularly occurs in people with liver disease, while Akkermansia muciniphila indicates good gut health. Moreover, certain bacteria are actually conspicuously absent in a disease." 

"Diversity of microorganisms is also important. The greater the variation, the more stable the system. Together, they protect the gut from pathogenic intruders. Each microbe has its own trick for that. Some remove food that the pathogen needs, while others produce substances that kill the harmful microbes." 

So you can control that ecosystem of microorganisms in the gut with nutrition?

"That is the idea. Obviously, you can have a yoghurt drink with probiotics to send live, healthy bacteria to your gut. But we mainly study how other nutrients stimulate the growth of beneficial microorganisms that are already in the gut. We call these food ingredients prebiotics. At WUR, we are therefore investigating at many levels how such ingredients affect the microbiome. For example, we study which dietary patterns increase the diversity of microorganisms in the gut, as well as how bacteria in the colon break down dietary fibre and how that affects their growth." 

What methods do you use for this? 

"We have various ways of studying changes in the microbiome, ranging from simple tests in the lab to sophisticated studies with human subjects. The simplest screening just involves some poo in a plastic plate with small pits, with the poo serving as an imprint of the gut microbiome. We then add a food ingredient and study what happens to the food ingredient. At the same time, we study how the microorganisms in the poo react to it, what substances they make and whether these are healthy or toxic. We are also working with an in vitro model: an artificial intestinal system." 

An artificial intestinal system, what does that involve? 

"It sounds quite graphic, but at first glance, it does not look like a human digestive system: it’s a cabinet with tubes, vials, syringes, and pumps. We introduce microorganisms that also live in our colon (read: poo) in the system, and they grow in it. It also mimics our intestines in other areas: from the peristaltic movements to mix and propel the digested food pulp, to our body temperature and the acidity of the colon. Several versions of these artificial intestines already exist, and at WUR we are now building a new, improved variant by combining existing technology. We call that new version TIMOHTI, which stands for The Incredible Mimic Of The Human Intestine. We feed that intestine all kinds of ingredients that also reach the colon in humans." 

What ingredients are they? 

"The colon is one of the last stops of the digestive system. The stomach kneads the food into a thick mush and the small intestine breaks down most proteins, fats and some carbohydrates and absorbs vitamins and minerals. What remains are for instance indigestible fibres (carbohydrates from plant products), sweeteners and non-degraded proteins. We feed the artificial intestine something similar. We then study the composition of the microbiome before and after feeding the test ingredients to the artificial intestine. In this way, we learn what effect those substances have on the microorganisms and their composition in the intestines. For example, microbes can make toxins from plant proteins that the small intestine does not fully break down and absorb." 

What major developments have you seen in the field over the past ten years? 

"Two things, in adjacent research fields: DNA sequencing and miniaturisation of chemical analysis. In the past, we had to culture microbes to identify them, but today we can directly ‘read’ their DNA. New technology now makes this happen really quickly and cheaply. That’s how we know exactly which microorganisms live in the gut. And thanks to modern analysis, we can tell with just a few micrograms of nutrient which substances are released during digestion." 

After twenty-five years, you still find the microbiome interesting. What do you find so fascinating about it? 

"I particularly like how much impact knowledge about the microbiome can have. If we fundamentally understand what ingredients do to the microorganisms in the gut, we can figure out how to use nutrition to steer our gut flora towards a healthy composition. This offers huge opportunities for the health of our society. I find that every bit of extra knowledge gives me more drive to keep going. We lead hectic lives and often eat unhealthily. With the right gut bacteria, we may be able to fix that. I love the fact that my research contributes to that." 

Can you cite an example? 

"When I worked at the Netherlands Organisation for Applied Scientific Research (TNO), I researched the ideal composition of a probiotic in tablet form, and my colleagues and I developed a coating that protected the microorganisms from the acidic and harsh conditions of the stomach to ensure they arrived alive in the intestines. This eventually led to a probiotic containing three microorganisms that is now on the market." 

So there’s already a lot of knowledge about the inhabitants of our gut. What don’t we know yet? 

"There’s still an awful lot we don't know. That’s partly because it is really difficult to culture gut microorganisms in the lab. This is because they cannot tolerate oxygen, a substance not found in our colon. But we need to culture microbes to really understand what they do and what they can do. Based on DNA, we can find out about seventy percent of the functions. This is because DNA contains the instructions for protein production and these proteins determine exactly what a microorganism does in its environment. But DNA doesn’t tell us everything. However, there are developments there too. With artificial intelligence, we can predict from the DNA code what such a protein looks like in three-dimensional terms, which may enable us to deduce what their function is. This opens new doors for our understanding of microbial systems." 

What would you investigate if you were given a blank cheque tomorrow? 

“I’d set up a large-scale study to map how all the different dietary fibres (re)shape our gut microbiota. Dietary fibre is a complex sugar structure mainly found in plant products, which microbes further digest for us. With sufficient resources, we could create a kind of catalogue: which microorganism benefits from which fibre? You can then develop more targeted nutrition or supplements that support healthy microbes and suppress harmful variants to boost gut health. That’s not just interesting for the food industry, but especially valuable for society." 

"But we aren’t there yet. We still know too little about the enzymes used by microorganisms to break down those fibres into smaller chunks. That knowledge is crucial to understanding why certain fibres promote health. To find out, we are building an AI program that predicts exactly what happens to each dietary fibre in the gut flora and how that affects the microbiome. Such an ambition requires a big team and years of commitment." 

Your expertise is also valuable for the food sector. How can companies collaborate with researchers like you? 

"We offer companies various options to test the effect of their food on the microbiome: a pipeline from simple screenings, the artificial intestine TIMOTHI, to clinical studies, with accompanying computer tools and visualisations to understand what is happening. Companies do not necessarily need to start at the beginning of that pipeline. They may already have done internal research and step in halfway. A good example is a bakery that uses grain that contains fibre fractions that are believed to be good for intestinal health. They want to test whether the way they process the grain makes that fraction more available. We will then explore that for them.  

In a clinical trial, for example, we study the effect of a fibre on healthy people or people with irritable bowel syndrome. We organise the subjects and conduct the study. One half gets a placebo, the other the product. Ideally, we’d like to do that in a crossover setup, so that each participant gets both treatments and is their own control." 

Can they come to you with any microbiome-related question? 

"We currently mostly offer a list of ideas and projects for which companies can apply. I hope to gradually work towards a different way, where customers come to us with a question or problem and we offer tailor-made solutions to solve their problem."